The long term benefit of coronary balloon angioplasty and atherectomy is limited by the considerably high occurrence of symptomatic restenosis (40-50%) 3 to 6 months following the procedure (Holmes et al. Am. J. Cardiol. (1984) 53:77C-81C). Restenosis is in part due to myointimal hyperplasia, a process that narrows the vessel lumen and which is characterized by vascular smooth muscle cell migration and proliferation (Forrester et al. J. Am. Coll. Cardiiol. (1991) 17:758-769). Medical therapies to prevent restenosis have been uniformly unsuccessful. Intravascular stents have been successfully used to achieve optimal lumen gain, and to prevent significant remodeling. However, intimal thickening still plays a significant role in stent restenosis.
The vascular architecture is maintained or remodeled in response to the changes in the balance of paracrine factors. One of the substances that participates in vascular homeostasis is endothelium derived nitric oxide (NO). NO is synthesized from the amino acid L-arginine by NO synthase. NO relaxes vascular smooth muscle and inhibits its proliferation. In addition, NO inhibits the interaction of circulating blood elements with the vessel wall. NO activity is reduced in hypercholesterolemia and after vascular injury. We have shown that administration of the NO precursor (L-arginine) has been shown to restore vascular NO activity in animals and in humans with endothelial vasodilator dysfunction due to hypercholesterolemia, atherosclerosis, or restenosis. Chronic enhancement of NO activity (by oral administration of L-arginine) is associated with a significant reduction in intimal thickening due to hypercholesterolemia and/or vascular injury. The observations associated with the oral administration are limited to systemic action. Cooke, et al, J Clin Invest 1992; 90:1168-72; McNamara, et al, Biochem Biophys Res Comm 1993; 193:291-6; Taguchi, et al, Life Sciences 1993; 53:PL387-92; Tarry and Makhoul, et al, Arterioscler Thromb 1994; 14:938-43; Hamon, et al, Circulation 1994; 90:1357-62; Wang, et al, J Am Coll Cardiol 1994; 23:452-8.
However, oral administration of L-arginine has potential systemic side-effects. These side-effects include increases in growth hormone and insulin release--this could, potentially, exacerbate hyperglycemia in patients with diabetes (which is a large segment of the patient population that requires balloon angioplasty for coronary or peripheral artery disease). In addition, there is evidence that in high doses (30 grams daily) oral L-arginine can increase the proliferation of tumor cells in human breast cancer. Accordingly, it would be beneficial to develop an approach which would allow one to enhance NO activity selectively in the vessel wall where this effect is needed without having systemic side-effects. We have developed an approach to diminish the incidence of restenosis resulting from angioplasty and atherectomy, using arginine to enhance NO activity in the vessel wall, while at the same time avoiding potential systemic side-effects.